A pilot induction regimen incorporating dinutuximab and sargramostim for the treatment of newly diagnosed high-risk neuroblastoma: A report from the Children's Oncology Group.
Authors: Sara Michele Federico, Arlene Naranjo, Fan Zhang, Araz Marachelian, Ami Vijay Desai, Hiroyuki Shimada, Steve E. Braunstein, Christopher L Tinkle, Gregory A Yanik, Shahab Asgharzadeh, Paul M. Sondel, Alice L. Yu, Michael Acord, Marguerite T. Parisi, Barry L. Shulkin, Steven G. DuBois, Rochelle Bagatell, Julie R. Park, Wayne Lee Furman, Suzanne Shusterman
Journal: Journal of Clinical Oncology (2022)

10003 Background: The addition of dinutuximab (DIN) in the post-consolidation setting led to improved event-free survival rates for patients with high-risk neuroblastoma. Chemoimmunotherapy including irinotecan, temozolomide, DIN and sargramostim (GM-CSF) in patients with recurrent or refractory neuroblastoma results in robust objective clinical responses. Evaluation of chemoimmunotherapy in the induction setting for patients with newly-diagnosed high-risk neuroblastoma (HR-NBL) warrants investigation. Methods: Children’s Oncology Group (COG) ANBL17P1 is a prospective, single arm, limited institution pilot study to assess the tolerability and feasibility of administering DIN (17.5mg/m 2 /dose, IV Days 2-5) and GM-CSF (250mcg/m 2 /dose, subcutaneous Days 6-count recovery) with COG Induction chemotherapy Cycles 3-5 for patients with newly-diagnosed high-risk neuroblastoma. The primary endpoint of tolerability included the number of toxic deaths and number of patients experiencing predefined unacceptable toxicities during Induction Cycles 3-5. Unacceptable toxicities included: hypotension requiring pressors &gt; 24 hours, respiratory toxicity requiring ventilatory support &gt; 24 hours, Grade 4 neuropathy that did not resolve prior to the next cycle, and failure to recover the ANC to &gt; 750 mm 3 by day 35. Feasibility was assessed as being able to receive &gt; 75% of planned DIN doses administered during Induction Cycles 3-5. Revised International Neuroblastoma Response Criteria (INRC) were used to assess end of Induction (EOI) response. Results: Forty-two eligible and evaluable patients with newly-diagnosed high-risk neuroblastoma enrolled at 8 sites (22 [52.4%] males; median age 3.3 years at diagnosis) from January 14, 2019 to June 4, 2020. The most common DIN related Grade &gt;3 toxicities observed during Induction Cycles 3-5 included fever (31.0%) and pain (9.5%). None of the patients experienced a toxic death or unacceptable toxicity during Induction Cycles 3-5. Thus, the regimen was deemed tolerable. Patients received 97.4% - 101.8% of the total DIN dose expected to be administered during Induction Cycles 3-5. Therefore, the regimen was deemed feasible. Thirty-eight of 42 patients completed the EOI evaluations, including 11 with complete response, 22 with partial response, 0 with minor response, 3 with stable disease and 2 with progressive disease. The overall EOI objective response rate (CR+PR+MR) was 86.8%. Conclusions: The administration of DIN and GM-CSF to COG Induction Cycles 3-5 for patients with newly-diagnosed high-risk neuroblastoma was tolerable and feasible. The objective response rate at EOI appears encouraging. This therapeutic regimen will be studied in a randomized phase 3 trial to further evaluate the efficacy of Induction phase chemoimmunotherapy for high-risk neuroblastoma. Clinical trial information: NCT03786783.